Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors

• Published in: Cancers 2024-05, Vol.16 (9), p.1707
• Main Authors: Denu, Ryan A, Joseph, Cissimol P, Urquiola, Elizabeth S, Byrd, Precious S, Yang, Richard K, Ratan, Ravin, Zarzour, Maria Alejandra, Conley, Anthony P, Araujo, Dejka M, Ravi, Vinod, Nassif Haddad, Elise F, Nakazawa, Michael S, Patel, Shreyaskumar, Wang, Wei-Lien, Lazar, Alexander J, Somaiah, Neeta
• Format: Article
• Language: English
• Subjects: Aurora kinase; Cancer; Comparative analysis; DNA; DNA damage; DNA repair; Fibroblast growth factor receptor 1; Gene deletion; Gene mutations; Genes; Genomics; Imatinib; Kinases; MAP kinase; Metastases; Metastasis; Mutants; Mutation; Next-generation sequencing; Oncology; p53 Protein; Patients; Platelet-derived growth factor; PTEN protein; Small intestine; Succinate dehydrogenase; Surgery; Tumor proteins; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers16091707

The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in , , or components of the succinate dehydrogenase (SDH) complex ( , , , and genes). A small fraction of GISTs lack alterations in , , and . We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs. We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients. Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5-191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a V600E mutation and two with loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with LOF mutations, one with fusion ( ), one with deletion, one with gain-of-function (GOF) mutation (K654E), one with LOF mutation (T367fs*), one with Aurora kinase A fusion ( ), and one with deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to / -mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.